Ablation therapy is a technique that uses temperature extremes to destroy or alter body tissue, for example cryoablation (which uses freezing temperatures) and radiofrequency ablation (“RFA,” which uses heat). Such undesirable tissue may be a tumor, cardiac tissue associated with arrhythmia, or diseased tissue. Ablation catheters are typically used to perform these techniques, and may generally include a power source, an energy and/or coolant source, and one or more ablation elements (such as a Peltier cooler, a balloon through which coolant circulates, or RF electrodes).
Even though ablation may be effective for treating some conditions, techniques such as cryoablation are not always the preferred mode of treatment for some diseases. However, adoption of ablation therapy by the medical community would be enhanced by improving the visualization of the “kill zone” (for example, the treatment region within the imaged iceball edge), increasing the size of the kill zone, and/or minimizing the incursion of collateral damage to non-target surrounding tissue. The effectiveness of ablation therapy is largely dependent on the ability of the physician to predict the critical isotherm (temperature at which complete cell destruction occurs) based on the imaging feedback (for example, of the edge of the iceball), and thus the outcome of ablation can vary greatly. Further, it can be difficult to destroy target tissue at the periphery of the treatment area (such as the iceball) while avoiding damage to non-target cells.
In an exemplary cryoablation procedure, the cryoablation elements are placed in contact with living body tissue to be ablated, and the temperature of the device at the cryoablation element is reduced to a temperature well below 0° C. After cooling of the cryoablation element begins, the temperature of the tissue in contact with the cryoablation element reaches the phase transition temperature and begins to freeze. As more heat is extracted, the temperature of the device continues to drop and the freezing interface (iceball) begins to propagate outward from the surface of the cryoablation element farther into the tissue, and this may result in a variable temperature distribution in both the frozen and unfrozen regions of the tissue.
The freezing interface continues to penetrate into the tissue until either the temperature of the cryoablation element rises (for example, when the flow of coolant within the device stops) or until the heat of the living tissue surrounding the frozen lesion reaches a steady state condition (that is, the heat becomes equal to the amount of heat removable by the cryoablation element). At this point, the frozen tissue has a temperature distribution that ranges from a low cryogenic temperature at the tissue/cryoablation element interface to the phase transition temperature on the outer edge of the frozen lesion. The temperatures in the unfrozen tissue range from the phase transition temperature at the margin of the frozen lesion to the normal body temperature. In typical cryoablation protocols, the cooling system keeps the tissue frozen for a desired period of time, and then the tissue is allowed to passively heat and thaw. Depending on the procedure, the tissue may again be frozen after thawing. The application of multiple freeze-thaw (FT) cycles has been shown to beneficially impact lesion size. However, multiple FT cycles also increases treatment time and may increase the likelihood of damaging non-target tissue.
Not only do temperature variations occur at and around the treatment site, but a variety of post-freezing effects occur in tissue that must be accounted for when optimizing the effects of cryoablation. When using a cryoablation device such as a cryoprobe at sub-zero temperatures to ablate an area of tissue, the thermal effects on each cell vary depending on its distance from the cryoprobe (closer cells experiencing lower temperatures and faster freezing rates). Complete tissue destruction may occur at temperatures below approximately −40° C., and temperatures at the edge of the iceball may be around −0.5° C. Uneven cell death rates may occur between −40° C. and −0.5° C.
Damage to cells from cryoablation may be by several mechanisms, including cellular, vascular, and immunological. At higher cooling rates near the cryoprobe, direct cell damage occurs due to the presence of ice crystals both within the cell and in the extracellular space within the tissue, up to a temperature of −0.5° C. At low cooling rates, the presence of extracellular ice causes solutes concentration outside the cell to rise, which in turn causes an osmotic imbalance of the cell membrane and dehydration of the cell. Vascular mechanisms of destruction may involve the shutdown of microvasculature after freezing and resultant ischemia, direct endothelial injury, thrombosis, free-radical formation, and inflammation. Immunological mechanisms of injury, such as when treating a tumor, may include the release of proteins into the blood stream. These proteins function as antigens, which may induce an immune reaction against the remaining tumor by stimulating immune cells to produce antibodies against tumor cells. Cryoablation may also increase the level of serum cytokines and induce maturation of dendritic cells, which then stimulate T-cells against the antigen.
Similarly, RFA destroys tissue instantaneously at temperatures greater than 60° C., with mechanisms of cell death including protein denaturation and destruction of blood vessels. Like cryoablation, the outcome of treatment is difficult to predict, which effectiveness being a function of treatment time, treatment temperature, and distance of tissue from the treatment element.
Certain chemicals have been shown to increase tissue sensitivity to temperature extremes. For example, the application of temperature-sensitizing adjuvants (“TSAs”) may increase the likelihood that cells within the periphery of the iceball that would otherwise remain viable will be destroyed by ablation treatment. These adjuvants (also referred to as “agents”) may include thermophysical adjuvants, chemotherapeutic adjuvants, cytokines or vascular-based adjuvants, and immunomodulators. Additionally, the application of low-current energy as an adjuvant may enhance the effects of cryoablation by increasing salt ion movement through the cell membrane, thereby increasing the salt imbalance occurring during freezing.
Sensitizing an area of target tissue before or during cryotherapy is therefore desired because an increase amount of damage may be incurred by the target tissue at higher temperatures, thus minimizing the energy requirements of the treatment device. Further, collateral damage may be mitigated. For example, cryotreatment of the heart may have unintended adverse consequences on the lungs, phrenic nerve, and other parts of the body because of the intense cold required to treat areas of the heart such as the pulmonary veins.
However, a convenient method of applying these adjuvants to target tissue in vivo is needed. For example, although adjuvants such as antifreeze proteins increase tissue sensitivity to cold, such results have been obtained after soaking excised tissue in the adjuvant, not through precise adjuvant application on living target tissue during a cryoprocedure.